Exploring stathmin control of cell survival through negative feedback of a JNK-dependent pathway  

Abstract

Previous studies demonstrated that stathmin, a microtubule destabilizing protein, promotes cell survival and/or prevents apoptosis, although the underlying molecular mechanism is unknown. Based on a recent work [1], we are testing the hypothesis that stathmin normally functions to keep the levels of active c-Jun N-terminal kinases (JNK) low. In this model, stathmin, phosphorylated by JNK, functions in a negative feedback loop to inhibit the JNK pathway and limit JNK activation. This model predicts that active JNK will rise in the absence of stathmin; prolonged activation of JNK would then trigger apoptosis. As a first test of whether stathmin regulates JNK activity to control cell survival, we found that treatment with either JNK-IN-8, a JNK inhibitor, or depletion of JNK1,2, prevented cell death in stathmin-depleted HeLa cells. Using a localization-dependent biosensor [2], we found that active JNK levels were higher in stathmin-depleted cells. Expression of a stathmin phosphomimic restored active JNK level and prevented apoptosis. These data support a model where phosphorylated stathmin, acting independently of the microtubule cytoskeleton, prevents JNK hyperactivation to promote cell survival.